Contents

Signs and symptoms

FTD is traditionally difficult to diagnose due to the heterogeneity of the condition. This heterogeneity means the signs and symptoms can vary dramatically between patients. Symptoms are classified into three groups which underlie the functions of the frontal and temporal lobes:

Behavioural variant FTD (bvFTD). Behavioural symptoms include lethargy and aspontaneity or oppositely disinhibition. Apathetic patients may become socially withdrawn and stay in bed all day or no longer take care of themselves. Disinhibited patients can make inappropriate (sometimes sexual) comments or perform inappropriate acts. Patients with FTD can sometimes get into trouble with the police because of inappropriate behaviour such as stealing or over speeding. Recent findings indicate that psychotic symptoms are rare in FTD, possibly due to limited temporal-limbic involvement in this disorder. Among FTD patients, only approximately 2% have delusions, sometimes with paranoid ideation; hallucinations are rare. This is significantly less than AD patients, where approximately 20% have delusions and paranoia.[2] See ref. "Psychotic symptoms."

Semantic dementia (SD). Some patients remain fluent with normal phonology and syntax but increasing difficulty with naming and word comprehension. It has been researched that some may even go through depression and lose their inhibitions and exhibit antisocial behavior.[3]

Recent studies indicates that patients that are diagnosed with FTD tend to overeat which results to binge eating.[4] These binge eating habitats are often associated with abnormal eating behavior including overeating, stuffing food, changes in food preferences (cravings for more sweets, carbohydrates), eating inedible objects and snatching food from others. Recent findings have indicated that the neural sturctures responsible for eating changes in FTD has been linked with atrophy in the right ventral insula, striatum and orbitofrontal cortex on structural MRI voxel-based morphometry (right hemisphere).[4]

Pathology

A number of case series have now been published looking at the pathological basis of frontotemporal dementia. As with other syndromes associated with frontotemporal lobar degeneration (FTLD), a number of different pathologies are associated with FTD:

TDP-43 pathology. Previously described as dementia with ubiquitin positive, tau- and alpha-synuclein negative inclusions with and without motor neuron degeneration. FTLD-TDP43 accounts for approximately 40% of FTD(± MND).

FUS pathology. Cases with underlying FUS pathology tend to present with behavioural variant FTD (bvFTD) but the correlation is by no means reliable enough to predict the post mortem pathology. FTLD-FUS represents only 5–10% of clinically diagnosed FTD.

Dementia lacking distinctive histology (DLDH) is a rare entity and represents the remaining small percentage of FTD that cannot be positively diagnosed as any of the above at post-mortem.

Evidence suggests that FTD selectively impairs spindle neurons,[8] a type of neuron which has only been found in the brains of humans, great apes, and whales.

Diagnosis

According to DSM-IV diagnosis is mainly clinical including changed behaviors, changes in language and others, using also image exams and neuropsychological tests.[9]

Structural MRI scans often reveal frontal lobe and/or anterior temporal lobe atrophy but in early cases the scan may seem normal. Atrophy is often asymmetric. Registration of images at different time points (e.g. one year apart) can show evidence of atrophy in two cross-sectional images that may be reported as normal. This is a useful diagnostic technique. However, many research groups are currently looking at ways of making an early diagnosis of FTD using other techniques (magnetic resonance spectroscopy, functional imaging, cortical thickness measurements etc.). FDG-PET scans classically show frontal and/or anterior temporal hypometabolism, which helps differentiate from Alzheimer's disease. The PET scan in Alzheimer's disease classically shows biparietal hypometabolism. Meta-analyses based on imaging methods have shown that frontotemporal dementia mainly affects a frontomedian network discussed in the context of social cognition or 'theory of mind'.[10] This is entirely in keeping with the notion that, on the basis of cognitive neuropsychological evidence, the ventromedial prefrontal cortex is a major locus of dysfunction early on in the course of the behavioural variant of frontotemporal degeneration.[11] The language subtypes of frontotemporal lobar degeneration (semantic dementia and progressive nonfluent aphasia) can be regionally dissociated by imaging approaches in vivo.[12]

Through recent findings it has been suggested that vivo brain imaging of tau aggregation in frontal temporal dementia using [F-18] FDDNP Positron Emission Tomography is more visual and has enhanced the ability to have a deeper understanding in frontal temporal dementia. Previous, fluorescent microscopy studies of Alzheimer’s disease (AD) brain specimens have shown that [F-18] FDDNP, displays and excellent visualization of interneurnnal neurofibrillary tangles (NFTs). With the aid of [F-18]FDDNP depicts that it is useful in imaging frontal temporal dementia. Visual images of [F-18] FDDNP-PET images emphasized a frontal signal in FTD compared to prominent temporal signals in AD. [F-18]FDDNP-PET has allowed the enhance visualization of tauopathies in patients. This has aided in differentiating FTD from parietal and temporal signals in AD. Further, the ability of [F-18] FDDNP to entitle tanopathies in vivo gives a tool for monitoring the effect of therapies to eliminate NFT accumulation.[13]

Genetics

A higher proportion of FTD cases seem to have a familial component than more common neurodegenerative diseases like Alzheimer's disease. More and more mutations and genetic variants are being identified all the time, so the list of genetic influences below may be outdated.

tau-positive frontotemporal dementia with parkinsonism (FTDP-17) is caused by mutations in the MAPT gene on chromosome 17 that encodes the Tau protein[14] It has been determined that there is a direct relationship between the type of tau mutation and the neuropathology of gene mutations. The mutations at the splice junction of exon 10 of tau lead to the selective deposition of the repeatative tau in neurons and glia. The pathological phenotype associated with mutations elsewhere in tau is less predictable with both typical neuroﬁbrillary tangles (consisting of both 3 repeat and 4 repeat tau) and Pick bodies (consisting of 3 repeat tau) having being described.The presence of tau deposits within glia is also variable in families with mutations outside of exon 10. This disease is now informally designated FTDP-17T. Through extensive research being conducted, FTD shows a linkage to the region of the tau locus on chromosome 17, but it is believed that there are two loci leading to FTD within megabses of each other on chromosome 17.[15]

FTD caused by FTLD-TDP43 has numerous genetic causes. Some cases are due to mutations in the GRN gene, also located on chromosome 17. Others are caused by VCP mutations, although these patients present with a complex mixture of Inclusion body myopathy, Paget's disease of bone, and FTD. The most recent addition to the list is a hexanucleotide repeat expansion in the promotor region of C9ORF72. Only one or two cases have been reported describing TARDBP (the TDP-43 gene) mutations in a clinically pure FTD (FTD without MND).

No genetic causes of FUS pathology in FTD have yet been reported.

Management

There is no known curative treatment for FTD. Supportive care is essential. Management of behavioural symptoms may be necessary (e.g. SSRIs for depression; atypical neuroleptics etc.).

Because FTD often occurs in younger people (i.e. in their 40's or 50's), it can severely affect families. Patients often still have children living in the home. Financially, it can be devastating as the disease strikes at the time of life that is often the top wage-earning years.[citation needed]